1-carboxamido pyrano(thiopyrano)(3,4-6)indole derivatives

ABSTRACT

Indole derivatives characterized by having a 1,3,4,9tetrahydropyrano(3,4-b)indole or 1,3,4,9tetrahydrothiopyrano(3,4-b)indole nucleus bearing a substituent in position 1, said substituent incorporating an acid, ester or amide function therein, are disclosed. The nucleus is further substituted at position 1 and may be optionally substituted at positions 3, 4, 5, 6, 7, 8, and 9. The derivatives are useful antiinflammatory, analgesic, antibacterial and antifungal agents and methods for their preparation and use are also disclosed.

United States Patent [1 1 Demerson et al.

[451 Oct. 22, 1974 l-CARBOXAMIDO PYRANO (THIOPYRANO) [3,4-611NDOLEDERIVATIVES [75] Inventors: Christopher A. Demerson, St.

Laurent, Quebec; Leslie G. Humber; Thomas A. Dobson, both of Dollard desOrmeaux, Quebec;

Ivo L. Jirkovsky, Montreal, Quebec, all of Canada [73] Assignee:American Home Products Corporation, New York, NY.

[22] Filed: June 1, 1971 [21] Appl. No.: 148,895

[52] U.S. Cl. 260/326.14 R, 260/315, 424/274 [51] Int. Cl C07d 27/56[58] Field of Search 260/3263 [56] References Cited OTHER PUBLICATIONSDorofeenko, et al., Chem. Abstr. 76: 153635e of Khim. Geterotsikl.Soedin, 1970, No. 2, 245-249, (Russ) Dorofeenko, et al., Chem. Abstr.76: 14384] of Kh im.

Geterotsikl Soedin, 1971, 7(3), 345-349,

Dorofeenko, G. N. et al., Khim. Geterotsikl, Soedin,

1969(3), 417-421, (Russ); C.A. 72:3412h (1970). Chemical Abstracts, Vol.72, 1970, para. 341211, pp. 312-313, Adding Pyrylium and Pyridine Ringsto Furan and lndole Derivs."

Primary Examiner-Joseph A. Narcavage Assistant Examiner-Ralph D. McCloud[5 7] ABSTRACT 8 Claims, N0 Drawings i c'fiioxiiiwmo PYRANO (THIOPYRANO)[3,4-6lINDOLE DERIVATIVES processes for their preparation and tointermediates used in these processes.

Notwithstanding the advances made during the last four decades in thedevelopment of agents for the treatment of inflammatory conditions,there still remains a need for effective agents without the side effectsassociated with the therapeutic agents presently used for this purpose.

The indole derivatives of this invention have been found to exhibitinteresting and useful pharmacodynamic properties without elicitingundesirable side effects. Notable attributes of this effect areantiinflammatory and analgesic activities. In addition the compounds ofthis invention exhibit antibacterial and antifungal properties.

SUMMARY OF THE INVENTION The indole derivatives of this invention arecharacterized by having a pyrano[3,4-b]indole or thiopyrano[3,4-b]indolenucleus bearing a substituent at position 1, said substituentincorporating an acid, ester or amide function therein. Thesederivatives may be represented by formula I in which R is selected fromthe group consisting of lower alkyl, lower alkenyl, lower alkynyl, lowercycloalkyl, phenyl, benzyl and 2-thienyl, R R, R and R are the same ordifferent and are each selected from the group consisting of hydrogenand lower alkyl, R is selected from the group consisting of hydrogen,lower. alkyl, hydroxy, lower alkoxy, benzyloxy, lower a]- kanoyloxy,nitro and halo, R is selected from the group consisting of hydrogen,lower alkyl and lower alkenyl, X is selected from the group consistingof oxy and thio, Y is selected from the group consisting of carbonyl,

I: in in it in which each of R, R, R, R, R and R is hydrogen or loweralkyl, and Z is selected from the group consisting of hydroxy, loweralkoxy, amino, lower alkylamino, di(lower)alkylamino and phenylamino.

The indole derivatives of this invention of formula I are prepared byreacting a compound of the formula 2 in which R R R, R, R and R are asdefined in the first instance and X is hydroxy or mercapto with acompound of formula Ii, Y and Z are as defined in the first instance, inthe presence of an acid catalyst.

DETAILED DESCRIPTION OF THE INVENTION The term lower alkyl" as usedherein contemplates both straight and branched chain alkyl radicalscontaining from one to six carbon atoms and includes methyl, ethyl,propyl, isopropyl, butyl, isobutyl, 2- methylpentyl and the like.

The term lower alkenyl" as used herein contemplates both straight andbranched chain alkenyl radicals containing from two to six carbon atomsand includes vinyl, ally], l-propenyl, methallyl, 2-ethyl-3- butenyl andthe like.

The term lower alkynyl as used herein contemplates both straight andbranched chain alkynyl radicals containing from two to six carbon atomsand includes ethynyl, proprargyl, l,l-dimethylpropargyl and the like.

The term lower cycloalkyl" as used herein contemplates saturated cyclichydrocarbon radicals containing from three to six carbon atoms andincludes cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term lower alkoxy as used herein contemplates both straight andbranched chain alkoxy radicals containing from one to four carbon atomsand includes methoxy, ethoxy, isopropoxy and the like.

The term "lower alkanoyloxy" as used herein contemplates both straightand branched chain al kanoyloxy radicals containing from two to sixcarbon atoms and includes acetoxy, propionyloxy, hexanoyloxy and thelike;

The term halo as used herein. contemplates halogens and includesfluorine, chlorine, bromine and iodine.

Where the term lower is used herein as part of the description ofalkylamino and dialkylamino, it contemplates one to six carbon atoms foreach alkyl group of such a radical and includes methylamino,nhexylamino, dimethylamino, diethylamino and the like.

The indole derivatives of formula I in which Z is hydroxy, the acidcompounds of this invention, form addition salts with suitable inorganicand organic bases. These salts possess the same activities as the parentacid compound when administered to animals and may be utilized in thesame manner. Suitable bases to form these salts include, for example,the hydroxides, lower alkoxides, carbonates and bicarbonates of sodium,potassium, calcium and magnesium, as well as the bases, ammonia,triethylamine, benzylamine and the like. The addition salts thusobtained are the functional equivalents of the parent acid compound inrespect to their therapeutic use. Hence, these addition salts areincluded within the scope of this invention and are limited only by therequirement that the bases employed ANTIINFLAMMATORY AND ANALGESICACTIVITY The useful antiinflammatory and analgesic activities of theindole derivatives of this invention may be demonstrated in standardpharmacologic tests, for example, the tests described by R. A. Turner in"Screening Methods in Phannacology," Academic Press, New York andLondon, I965, pp. 152-163 and pp. I-I17, respectively.

More particularly, the antiinflammatory activity of the compounds ofthis invention may be readily demonstrated in a modification of theFreunds adjuvant test,

the adjuvant induced acute edema test as described by J. R. Boissier, etal., Therapie, 25, 43 (1970). This test is known to correlate well withdata derived from clinical results with humans. Boissier et al., havedemonstrated this correlation with such clinically active compounds asphenylbutazone, mefenamic acid, indomethacin, aspirin, hydrocortisoneand prednisolone.

More particularly exemplified, a substantial antiinflammatory effect forthe compounds listed below is demonstrable at oral doses of 100 mg/kg orless in this acute edema test. In this test male rats are treated withthe test compound one hour before the injection of Freunds adjuvant intothe paw (day 0). The rats are then treated with the same dose of thetest compound for the next 3 days. The antiinflammatory effect of thetest compound is measured by the reduction of pedal inflammation, seeTurner cited above, and expressed as a percent inhibition from adjuvantinjected control rats on day 3.

ceptable excipients, such as starch, milk sugar and so forth. They mayalso be administered orally in the form of solutions in suitablevehicles such as vegetable oils.

The dosage of the indole derivatives of this invention will vary withthe particular compound chosen and form of administration. Furthermore,it will vary with the particular host under treatment. Generally, thecompounds of this invention are administered at a concentration levelthat affords protective effects without any deleterious side effects.Theseantiinflammatorily analgesically effective concentration levels areusually obtained within a therapeutic range of 1.0 mg to 500 mg/kg perday, with a preferred range of 10 to I00 mg/kg per day.

ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY The indole derivatives of thisinvention also exhibit utility as antibacterial agents against a numberof grampositive and gram-negative microorganisms, such as,Staphylococcus pyogenes, both penicillin sensitive and penicillinresistant, Streptococcus faecalis, Escherichia coll, Aerobacteraerogenes, Salmonella pullorum, Pseudomonas aerugenosa, Proteusmirabilis, Proteus vulgaris, Klebsiella pneumoniae and Serratiamarcescens and as antifungal agents against a number of pathogenic fungisuch as, Candida albicans, Microsporum gypseum and Trichophytongranulosum, in standard tests for antibacterial and antifungal activity,such as those described in Antiseptics, Disinfectants, Fungicides andSterilization, G. F. Reddish, Ed., 2nd ed., Lea and Febiger,Philadelphia, I957 or by D. C. Grove and W.

The lack of side effects for the compounds of this invention may bedemonstrated by standard acute toxicity tests (see Turner cited above)and by prolonged administrationof the compound to warm-blooded animals.

When the present indole derivatives of this invention are employed asantiinflammatory and analgetic agents in warm-blooded animals, e.g.,rats, they may be administered orally, alone or in dosage forms, i.e.,capsules or tablets, combined with pharmacologically ac- A. Randall inAssay Methods of Antibiotics, Med. Encycl. Inc., New York 1955.

For example, by employing a test like the serial broth dilution, seeGrove and Randall, cited above, in which dilutions of the compounds ofthis invention in nutrient broth are inoculated with the microorganismsor fungi, described above, incubated at 37C. for 2 days, respectively,and examined for the presence of growth, it may be shown that I-methyll,3,4,9-tetrahydropyrano- [3,4-b]indoIe-l-propionic acid is able toinhibit growth totally in this system of Proteus vulgaris, Klebsiellapneumoniae and Serratia marcescens at a concentration of 100 meg/ml. orless.

When the compounds of this invention are employed as antibiotic orantifungal agents in warm-blooded animals, e.g., rats, they may beadministered alone or in combination with pharmacologically acceptablecarriers. The proportion of the compound is determined by the solubilityand chemical nature of the compound, chosen route of adminstration andstandard biological practice. For example, they may be administeredorally in solid form containing such excipients as starch, milk sugar,certain types of clay and so forth. They may also be administered orallyin the form of solutions or they may be injected parenterally. Forparenteral administration they may be used in the form of a sterilesolution containing other solutes, for example, enough saline or glucoseto make the solution isotonic.

The dosage of the present therapeutic agents as antibiotic or antifungalagents will vary with the form of administration and the particularcompound chosen. Furthermore, it will vary with the particular hostunder treatment. Generally, treatment is initiated with small dosagessubstantially less than the optimum dose of the compound. Thereafter,the dosage is increased by small increments until the optimum effectunder the circumstances is reached. ln general, the compounds of thisinvention are most desirably administered at a concentration level thatwill generally afford antibacterially or antifungally effective resultswithout causing any harmful or deleterious side effects and preferablyat a level that is in a range of from about 1.0 mg. to about 1,000 mg.per kilo per day, although as aforementioned variations will occur.However, a dosage level that is in the range of from about mg. to about500 mg. per kilo per day is most desirably employed in order to achieveeffective results.

In addition, the agent may be employed topically. For topicalapplication they may be formulated in the form of solutions, creams, orlotions in pharmaceutically acceptable vehicles containing 0.1-5percent, preferably 2 percent, of the agent and may be administeredtopically to the infected area of the skin.

Also the antibacterial properties of the compounds of this invention maybe utilized for washing equipment in hospitals, homes and farms,instruments used in medicine and bacteriology, clothing used inbacteriological laboratories, and floors, walls and ceiling in rooms inwhich a background free of gram-positive and gramnegativemicroorganisms, such as those listed above, is desired. When employed inthis manner the compounds of this invention may be formulated in anumber of compositions comprising the active compound and an inertmaterial. In such compositions, while the compounds of formula I of thisinvention may be employed in concentrations as low as 500 p.p.m., from apractical point of view, it is desirable to use from about 0.10 percentby weight, to about 5 percent by weight or more.

The formulations that may be used to prepare antiseptic wash solutionsof the compounds of this invention are varied and may readily beaccomplished by standard techniques, see for example, "RemingtonsPractice of Pharmacy, E. W. Martin et al., Eds, 12th ed., MackPublishing Company, Easton, Pa., 1961, pp. 1,121 1,150. in general, thecompounds may be made up in stock solutions. They can also be formulatedas suspensions in an aqueous vehicle. These make useful mixtures fordecontaminating premises. Also, aqueous vehicles containing emulsifyingagents, such as sodium lauryl sulfate, and relatively highconcentrations, e.g., up to about 5 percent by weight, of the compoundsmay be formulated by conventional techniques.

A typical antiseptic preparation useful for disinfecting floors, walls,ceiling, and articles in a contaminated room may be prepared by adding 5to 25 g. of N,N,ltrimethyl-l ,3,4,9-tetrahydropyrano[ 3 ,4-b]indolelacetamide to a mixture of to 300 g. of polyethylene glycol 1,540 and 150to 300 g. of polyethylene glycol 300. The resulting mixture is stirredwhile a solution of 1 to 10 g. of sodium lauryl sulfate in 300 to 400ml. of water is added portionwise. The article to be disinfected iscoated or immersed in the preparation for a prolonged time, for example,1 hour, and then rinsed with sterile water.

PREPARATION OF INDOLE DERIVATIVES For the preparation of the indolederivatives of this invention we prefer to use as starting materials thecompounds of the general formula. II.

in which R R, R, R and R are as defined in the first instance and X ishydroxy or mercapto.

The starting materials of formula 11 in which X is hydroxy are eitherknown, for example, tryptophol, de' scribed by H. R. Snyder and F. .l.Pilgrim, .I. Am. Chem. Soc. 70, 3,770 1948), or they may be obtained bythe following process:

III. IV.

With reference to this process phenylhydrazines of formula III and thehydroxyaldhyde of formula IV are reacted together according to theconditions of the Fischer lndole Synthesis, for example, see P. L.Julian, E. N. Myer and H. C. Printy, Heterocylic Compounds, R. C.Elderfield, Ed., Vol. 3, John Wiley and Sons, lnc., New York, 1952, pp.8 1 l, to form the desired starting material (11, X OH).

The phenylhydrazines of formula 111 are either known or may be preparedaccording to known methods. A convenient method involves thediazotization of the appropriately substituted aniline to give thecorresponding diazo derivative. The latter compound is then reduced withstannous chloride or sodium sulfite to give the correspondingphenylhydrazine, see L. F. Fieser and M. Fieser, Advanced OrganicChemistry, Reinhold Publishing Corporation, New York, 1961, p. 734.

The hydroxyaldehydes of formula IV are either known, see for example,Rodds Chemistry of Carbon Compounds," S. Coffey, Ed, Vol. 1 d, 2hd ed.,Elsevier Publishing Co., Amsterdam, 1965, pp. 44 49, or they may beprepared according to known methods. A convenient method involvesreduction of an appropriate lactone of formula with bis-(3-methyl-2-butyl )borane, H. C. Brown and D. B. Bigley, J. Am. Chem.Soc., 83, 486 (1961), diisobutyl aluminum hydride, L. l. Zakharkkin andl. M. Khorlina, Tetrahedron Letters, 619 1962) or sodium aluminumhydride, L. I. Zakharkin et al., Tetrahedron Letters, 2,087 (1963). Theappropriate lactones utilized in this condensation are eithercommercially available, for example, fi-valerolactone,a-methyl-butyrolactone, or they are described with a variety of methodsfor their preparation in organic chemistry textbooks; such as thetextbooks, Methoden der Organischen Chemie, Houben-Weyl, E. Muller, Ed.,Vol. Vl/2, Georg Thieme Verlag, Stuttgart, 1963, pp. 561 852 or L. F.Fieser and M. Fieser, Advanced Organic Chemistry, cited above.

Alternatively, the starting materials of formula 11 in which R R and Rare hydrogen and X is hydroxy may be prepared by lithium aluminumhydride reduction, N. G. Gaylord, Reduction with Complex Metall-lydrides," lnterscience Publishers, lnc., New York, 1956, pp. 322 370,of compounds of formula V described by T. Y. Shen, U.S. Pat. No.3,161,654, Dec. 15, 1964:

HCOOR" wherein R is lower alkyl and R and R are as defined in the firstinstance.

The starting materials of formula ll in which X is mercapto and R R, R",R and R are as defined in the first instance may be obtained by thefollowing process: The appropriate compound of formula 11 (X OH),described above, is treated with phosphorus tribromide in an inertsolvent, for example, ether or carbon tetrachloride, to afford thecorresponding 3-(2- bromoethyl)-indole derivative. The latter compoundis then converted to the desired starting material of formula 11 (X' SH)by a procedure similar to that described by N. N. Suvorov and V. N.Buyanov, Khim.- Farm. Zh., l, 4 (1967), [Chem Abstr. 67, 73474a (1967)],for converting 3-(2-bromoethyl)-indole to idole-3-ethanethiol (11; R R,R R and R H and X SH). Accordingly, the appropriate 3-(2-bromoethyl)-indole derivative is treated with sodium or potassiumthiosulfate to afford the corresponding sodium or potassiuml3-(3-indolyl)ethyl sulfate derivative, respectively, which on treatmentwith strong alkali for example, sodium or potassium hydroxide, istransformed into the corresponding bis-[w-(3-indolyl)ethyl]disulfidederivative. Reduction of the latter compound with lithium aluminumhydride gives the desired compounds of formula 11.

It should be noted that the preceding process is not entirely practicalfor the preparation of the compounds of formula 11 in which X ismercapto and R is hydroxy or lower alkanoyloxy. For this reason, thepreferred starting materials of formula 11 for the ultimate preparationof the compounds of formula 1 in which R is hydroxy or lower alkanoyloxyand X is thio are the corresponding compounds of formula 11 in which Ris benzyloxy, readily prepared by this process. When the lattercompounds are used as starting materials in this manner, they are firstsubjected to the process (11 V] Vll), described below. Subsequently, thehenzyloxy group is removed by hydrogenation, in the presence of acatalyst, for example, 10 percent palladium on carbon, to afford thecorresponding compound of formula I in which R is hydroxy. The lattermay be converted if desired to the corresponding compound of formula Iin which R is lower alkanoyloxy by conventional means, for example, bytreatment with the appropriate lower alkanoic anhydride preferably inthe presence of pyridine. Likewise, it should be noted that similar useof the starting materials of formula 11 in which X is hydroxy and R isbenzyloxy to obtain the corresponding compound of formula 1 in which Ris hydroxy or lower alkanoyloxy is preferred.

For the preparation of the acid and ester compounds of this invention offormula 1 in which R is hydrogen, Z is hydroxy or lower alkoxy and R R,R, R, R R", X and Y are as defined in the first instance, we have foundthat the following, hitherto undisclosed process is both practical andconvenient:

in which R, R R, R, R R, R, X, Y and Z are as defined in this instance,X is hydroxy or mercapto and R is hydrogen or lower alkyl. (Forconvenience and clarity these particular acid and ester compounds offormula I are represented above as formula V").

With reference to the above scheme the starting maand R is hydrogen, itis preferable with respect to yield to first condense the appropriate Ll-ketoester of formula VI rather than the corresponding B-ketoacid andthen hydrolyze the resulting ester product to give the desired acidcompound.

Moreover, in the general practise of this invention it is often moreconvenient to prepare the acid compounds of formula VII by using theketoester instead of the ketoacid in this process and then hydrolyze theresulting ester product to the desired acid, the reason being simplythat the ketoesters are generally more readily available eithercommercially or by synthesis.

The hydrolysis of compounds of formula VII in which R is lower alkyl totheir corresponding acids of formula VII is readily effected bytreatment with a suitable alkali, for example, potassium hydroxide orsodium carbonate, in aqueous methanol or aqueous ethanol.

In practising the condensation (II V1 VII) we have found it preferableto use a solvent as a reaction medium. Any solvent inert to the reactionconditions may be used. Suitable solvents include benzene, toluene,diethyl ether, dioxan, tetrahydrofu'ran, methylene dichloride, carbontetrachloride and the like. Benzene and tetrahydrofuran are especiallyconvenient and practical for this use. A variety of suitable acidcatalysts may be used for this condensation, for example, the type ofcatalyst used in a Fischer lndole Synthesis, i.e., p-toluenesulfonicacid, phosphorus pentoxide, boron trifluoride, zinc chloride,hydrochloric acid and sulfuric acid and the like. p-Toluenesulfonicacid, boron trifluoride and phosphorus pentoxide are included among thepreferred acid catalysts. The amount of acid catalyst used is notespecially critical and may range from 0.01 molar equivalents to 100molar equivalents; however, a range of from 0.1 to molar equivalents isgenerally preferred. The time of the reaction may range from 10 minutesto 60 hours, with the preferred range being from V2 to 24 hours. Thetemperature of the reaction may range from C. to the boiling point ofthe reaction mixture. Preferred temperature ranges include 20 to 120C.

The or, 3-, 'yand fi-ketoacids and -ketoesters of formula VI are eitherknown, for example, ethyl pyruvate, levulinic acid, ethyla,a-dimethylacetoacetate, B,,8-dimethyllevulic acid and benzoylaceticacid or they may be prepared by known methods described in generalorganic chemistry textbooks. For example, a comprehensive review on theproperties and preparation of such 01-, 6-, yand o-ketoacids and-ketoesters may be found in Rodds Chemistry of the Carbon Compounds,cited above, Vol. 1d, pp. 226 274.

Alternatively, the acid compounds of formula I in which R is hydrogen, Zis hydroxy and R, R, R, R, R, R, X and Y are as defined in the firstinstance may be prepared by the following process:

10 in which Y is CH C(R)(R")CH C(R)(R )C(R)(R)CH or C(R)R")C(R)(R)C(R,)(R)CH R is hydrogen or lower alkyl, Z is hydroxy and R, R, R, R", R R,X and Y are as defined in the first instance.

With reference to this alternative process a starting material offormula II is condensed with a ketoalcohol lower alkyl ester (VIII) inthe presence of a suitable acid catalyst according to the conditionsdescribed above for the condensation (II V1 VIII). The ketoalcohol loweralkyl esters are either known, for example, acetonyl acetate orS-acetoxypentan-Z-one, or may be prepared by known methods, forinstance, see Rodds Chemistry of the Carbon Compounds, cited above, Vol.1d, pp. 49 54. In this: manner the condensation product of generalformula IX is obtained. Hydrolysis of this product with an aqueousalcoholic solution of a suitable alkali, for example, sodium hydroxidein aqueous methanol, affords the corresponding primary alcohol X. Theprimary alcohol is then oxidized to the corresponding aldehyde offormula XI. Although a variety of methods are known for the oxidation ofa primary alcohol to its corresponding aldehyde, see for example, RoddsChemistry of the Carbon Compounds, cited above, Vol. 1c, pp. 4 10, wehave found that the method of K. E. Pfitzner and J. G. Moffat, J. Am.Chem. Soc., 87, 5,670 (1965) using N,N-dicyclohexylcarbodiimide anddimethyl sulfoxide in the presence of a suitable acid, for example,trifluoroacetic acid, to be both efficacious and convenient in thiscase. Subsequently the aldehyde XI may be converted to the desired acidcompounds of formula I by a variety of oxidizing agents, includingsilver oxide, alkaline permanganate, hydrogen peroxide, per acids andthe like. In this case we prefer to use silver oxide according to themethod of M. Dele'pine and P. Bonnet, Compt. rend, 149, 39 (1909).

The amide compound of this invention of formula I in which R" ishydrogen, Z is amino, lower alkylamino, di(lower)alkylamino andphenylamino and R, R R, R, R, R, X and Y are as defined in the firstinstance, may be prepared from their corresponding acid compounds offormula 1 (compounds of formula VII in which R is hydrogen, describedabove) by treatment of the latter compounds with a lower alkylchloroformate, preferably ethyl chloroformate, in the presence oftriethylamine, affording the corresponding mixed anhydride, which isconverted by treatment with the appropriate amine, such as ammonia,aniline or a suitable alkylamine or dialkylamine, to the desired amidecompound of formula 1.

Alternatively, these amides of formula I may be prepared from thecorresponding esters of formula 1 (compounds of formulae VII, in which Ris lower alkyl, described above) by treatment of the latter compoundswith the appropriate amine according to known methods, for example, seeA. L. J. Beckwith in The Chemistry of Amides," J. Zalicky, Ed,Interscience Publishers, New York, 1970, pp. 96 105.

Again alternatively, the amide compounds of formula I in which R ishydrogen, Z is amino, lower alkylamino, di(lower)alkylamino, andphenylamino and R, R, R", R, R R, X and Y are as defined in the firstinstance, may be prepared by the condensation of an appropriate startingmaterial of formula II with an appropriate 01-, 8-, yor S-ketoamide inthe presence of a suitable acid catalyst according to the conditionsdescribed above for the condensation (11 Vl +Vl1). The ketoamidesrequired for this condensation are either known, for example, pyruvamideor a,a-dimethylacetoacetamide, or they may be prepared by known methods,for instance, see Rodds Chemistry of the Carbon Compounds," cited above,Vol. 1d, pp. 226 274.

The alkylated acid and ester compounds of this invention of formula 1 inwhich R is lower alkyl or lower alkenyl and Z is hydroxy or loweralkoxy, are prepared readily from the above described, correspondingacid or ester compounds of formula 1 in which R is hydrogen. Thisconversion involving the N-alkylation of the indolic nitrogen iseffected by treatment of the latter compounds with an appropriate loweralkyl or lower alkenyl halide in an inert solvent in the presence of anacid acceptor. Preferred conditions for effecting this conversioninclude the use of sodium hydride as an acid acceptor andtetrahydrofuran as the inert solvent.

The N-alkylated amide compounds of formula 1 in which R is lower alkylor lower alkenyl and Z is amino, lower alkylamino, di(lower)alkylaminoor phenylamino are preferably prepared by either treatment of theN-alkylated acid compounds of formula 1, described above, with a loweralkyl chloroforrnate followed by treatment with the appropriate amine,or treatment of the N-alkylated ester compounds of formula 1, describedabove, with an appropriate amine, in the manner described previously forthe preparation of the amide compounds of formula 1 in which R" ishydrogen.

Finally, it is the intention to cover all changes and modifications ofthe embodiment of the invention herein chosen for the purpose ofdisclosure which are within the scope and spirit of this invention. Suchchanges and modification include those variations which depend on wellknown interconversions of acids and esters or alternation of the orderof N-alkylation in the processes disclosed herein.

For example, in preparing the N-alkylated acid, ester or amide compoundsof formula 1 in which R is lower alkyl or lower alkenyl, the changing ofthe order of the N-alkylation step, as depicted in the embodiment ofthis invention, by the act of N-alkylation of the starting materials offormula 11 and subjecting the products thereof to treatment with anappropriate ketoacid or ketoester of formula V1 or a ketoamide,according to the teaching of the present disclosure, would not departfrom the spirit or scope of this invention.

Likewise, the preparation of the N-alkylated amide compounds of formula1 in which R is lower alkyl or lower alkenyl and Z isdi(lower)alky1amino by N- alkylation of the corresponding compounds offormula 1 in which R is hydrogen, is considered to be a process whichwould be functionally equivalent to the process embodied herein for thepreparation of these compounds.

The following examples will illustrate further this invention.

EXAMPLE 1 IMETHYL- l .3,4,9-TETRAHYDROPYRANO[ 3,4- b]lNDOLE-l-ACETICACID (1; R CH R R, R, R, R AND R"= H, X =0, Y =CH CO AND Z= OH) Ethylacetoacetate (23.4 g., 0.18 moles) is added to a solution of thestarting material of formula 11, tryptophol (10.0 g., 0.06 moles), in200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonicacid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate(Molecular Sieves No. 4) are added. The mixture is subjected to refluxfor 30 minutes, 600 mg. more of p-toluenesulfonic acid is added andrefluxing continued for 2 hours. The molecular sieves are collected andthe benzene solution washed successively with 5 percent sodiumbicarbonate and water, dried over sodium sulfate, and evaporated underreduced pressure to dryness affording an oil. The oil is subjected tochromatography on silica gel. Elution with 5 percent ether in benzeneyields the ester, l-methyl-1,3,4,9-tetrahydropyrano-[3,4-b]indole-l-acetic acid ethyl ester, as an oil, 'ys 1715 cm".

Hydrolysis of this ester to the title compound is effected as follows:The ester is dissolved in 230 ml. of methanol. To this is added 10 g. ofKOH in 30 ml. of H 0 and the solution is allowed to stand at roomtemperature overnight. The methanol is evaporated, water added and thesolution washed with benzene. The aqueous phase is acidified with 6NHCl, and extracted with benzene. This organic phase is washed withwater, dried over sodium sulfate and evaporated to dryness to give anoil, which is crystillized from benzene containing a trace of petroleumether to afford the title compound, m.p. 150 152C., y,,,,,, 3 3325 and1705 cm".

An equivalent amount of methyl acetoacetate may replace ethylacetoacetate in the procedure of this Example. ln this case,1-methy1-l,3,4,9- tetrahydropyrano[3,4-b1indole-acetic acid methylester, m.p. 87 90C. after recrystallization from benzenehexane, isobtained as the ester.

An equivalent amount of propyl acetoacetate may replace ethylacetoacetate in the procedure of this Example. ln this case,1-methyl-1,3,4,9- tetrahydropyrano[3,4-b]indole-1-acetic acid propylester is obtained as the ester.

EXAMPLE 2 l-METHYL-l ,3,4,9-TETRAHYDROPYRANO[ 3 ,4- b]1NDOLE-l-PROP1ONICAClD (l; R CH R R, R, R, R AND R H, X O, Y CH CH CO AND Z OH) A mixtureof the starting material of formula 11, tryptophol (500 mg), levulinicacid (580 mg.), 75 ml. of benzene, 1.7 g. of phosphorus pentoxide andabout 0.5 g. of diatomaceous earth (Celite) is stirred megnetically atroom temperature for 15 minutes and then at 70C. for 1 Va hr. Thereaction mixture is filtered. The filtrate is washed three times with 5NNaOH; the combined aqueous phase is washed twice with ether and thenrendered acidic with cold 50 percent HCl. The aqueous phase is extractedwith chloroform. The chloroform extract is dried (Na SO,) and evaporatedto dryness. The residue is crystallized from ethyl acetatepetroleumether to afford the title compound, m.p. 104 C., nmr(CDC1 8 1.47 (3H),2.18 (4H), 2.74 (2H), 3.96 (2H), 7.18 (4H), 7.85 (1H), 9.60 (1H).

The above title compound is also obtained by following the procedure ofExample 1 but replacing ethyl acetoacetate with an equivalent amount ofethyl levulinate. In this case l-methyl-1,3,4,9- tetrahydropyrano[ 3,4-b]indolel -propionic acid ethyl ester, m.p. 116 118C., y f 1716 cm,after crystallization from benzene-petroleum ether, is obtained as theester prior to hydrolysis.

EXAMPLE 3 1 (6H), 7.35 (multiplet, 4H), 8.71 (ll-l), l0.3l (ll-l), afterrecrystillization from benzene-hexane.

The procedures of Examples 1, or 3 may be followed to prepare othercompounds of formula I in which R,

-M R, R, R, R R", X and Y as defined in the firstin-TETRAHYDROTHIOPYRANOl3t4-bllNDoLE-lstance, R is hydrogen and Z ishydroxy. Examples of ACETIC ACID 3, R3, R6 AND such compounds of formulaI are listed Tables I and II. R7 H, X Y CH2CO AND Z In each of theseexamples an equivalent amount of the ]ndo|e 3 ethanethio] (15 and methylacetoac starting material of formula ll listed therein is used instateare mixed with 5 of benzene and the Solution stead of the startingmaterial of formula ll described in heated for 30 m (bath temperaturethe procedures of Examples 1 and 3. Note that in each p T0]ueneSu]fonicacid (015 is added and the reac of these examples the ester obtainedprior to hydrolysis tion mixture is subjected to reflux and stirring for12 i cofrespondmg ester compound f hours. Water formed in the reactionmixture during this whlch Z a lower alkmiy of the product hsied l periodis collected by a water separator. After cooling the alkyl g of Samlower alkoxy bemg der'ved the benzene solution is washed with a 10percent solufrom the R P of the ketoester of formula W tion of sodiumbicarbonate, water, saturated brine and Ployed therem' dried over sodiumsulfate. Evaporation of the benzene Similarly, the procedure of Example2 may be used solution yields the ester, l-methyl-1,3,4,9- to preparethe products listed in Tables I and ii. in thistetrahydroth1opyrano[3,4-b1indole-l-acetic acid case an equivalentamount of the starting material of methyl ester as a semi-solid, 'y 81715 cm". formula ll, listed therein is used instead of the startingThis ester is then treated with aqueous alcoholic material of formula IIdescribed in Example 2 and an KOH in the manner described for the estersin Example equivalent amount of the corresponding ketoacid of l and 2 toafford the title compound, m.p. 147 formula VI of the ketoester offormula Vl listed therein 149C, nmr (CDCl 61.86 (S, 3H), 3.06 and 8.12is used instead of the said ketoester.

" TABLE I Ketoester of Formula VI Product: [(pi'efix 0 listed below) -1,3, 4, 0- ll tetmhydropyrano- Starting material of Formula II R1C-Y-O R[3, 4-b]ir tdole-1- (suffix listed bc10w)] Ex. R R3 R4 R5 R5 X R1 Y R116prefixl/suiiix 4 H H H H H O OH; 00 021115 l-methxcrilcarbox- 5 on, H II11 II 0 02115 o0 C2115 1cthyl-3n tetl1yl// carboxylic acid.

6 ..11C3H7 H H H 5-011 0 n-C II CO CH: 1,3dilsopropyl-6-methyl/curboxylic acid.

7 CH3 cm H H 5-011 o G1IaCII=C1I ()0 CH3 3.3-dimet11yi-6-hydroxy-l-(iropenyD/lcaroxylic acid.

8 H H H II 70,115 0 H050 o0 CH3 8-ethyl-l-ethynylll carboxyhc acid.

9 H H 2-0311, H II o 0o CH3 l-cycloprop 1-4- isopropyl lcarboxylic acid.

10..." CH3 CH3 CzHs CzHs H O CO CH3 l-cyclopentyl-Mk dleth 3-dimethyl/lcarbox ylic acid.

11-... H H H H H O CO CH; i-phenyll/carboxylic acid.

oH 1-1; 1-3- th 1- 12 CH3 02115 H H 0 CH2 0o 3 eg z r r g ylic acid.

130-" H H H H 6 Cl n O CO t ahig ii ybflcarboxylic acid.

14-.-" H H CH3 H H 0 CH3 CH2CO CzHs 1,4-(1iII18l3l1YI/l o H l-g lsi rfil e ic acid 15- H H H H H 0 C2115 011200 2 5 MR 16..... H H H H H On-CaH7 CHZCO CzHrt l-pro pylllacetic aci M.P. Hts-151 o.

T11-.. H 'H H H H 0 103111.; .Q....'. @1366 ""o'ziii," i 'isii irbfii/lactic" sm g, M.P.150-

1s CH3 H H H H o CH2=CIICH2 011200 02m 1-rti1} 1 -a m t h 1// C l l 19..C113 H H H H o 11-CsH1 011200 @2115 3- 1tn yi-im 1/ acetic acid; M1. -80C. (Isomer A), Mi. 146-148 C. (Isorner 13).

2o CH3 H 0211, OH; H 0 H020 OHzCO c2115 -ethyi l-etbynfl-B-methyll/acetic acid, ,CHOlri max. 3,300, 2,135, 1,710 cmr TABLEIICoutinued Ketocster of Formula VI Product: [(Prefix listedl)c1ow)-1,2,4,9- O tcirahydrothicpy- A rmio-[3,4-h]lndolo-1- Startingnmtcrlal 01 Formula II R -Y-OR (suillx listed l)(lW)] EX. 1! R R R R X BY R Sullixl/l'rviix aci i66 l1 11 ll 11 7-011 S .....d0C(CIIBMCHQOGJHMCO CzHs l-bonzyl-S-hydroxya,oz,'y,'Y-1J6l3lfl.-methyl/Ibutyric acid.

thicnyD/Ibutyric 5 acid.

188.... 0 11 II 0 11 (4H5 G-Ol S Same as above CHqCHzC (CrIImCO C 1157-C11l0r0-a,a,3,4,4-

EXAMPLE 169 1-METHYL-l,3 ,4,9-TETRAHYDROPYRANO[ 3,4-b]1NDOLE-1CARBOXALDEHYDE (X1; R CH R R, R", R AND R H, AND Y CO) Amixture of the starting material, tryptophol (32.2 g, 0.2 mole),acetonyl acetate (23.2 g, 0.2 mole) and 3.2 g of p-toluenesulfonic acidin 500 ml of benzene is refluxed for 1% hr. in the presence of aDean-Stark water trap. The benzene solution is washed with 5 percentsodium bicarbonate, water, dried and evaporated to afford an oil. Theoil is subjected to chromatography on a silica gel column using percentethyl acetate in benzene as eluent. The acetate, l-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-l-methanol, acetate is obtained as an oil,nmr(CDCl 8 1.52(S,3H), 2.08(S,3H), 4.35(2H).

This acetate is dissolved in 250 ml of methanol and stirred at roomtemperature. To this solution is added dropwise ml of lON NaOH.Hydrolysis is immediate. Most of the methanol is removed under reducedpressure, and water is added. The mixture is rendered neutral andextracted with chloroform. The chloroform extract is dried andevaporated to afford the primary alcohol, l-methyl-l,3,4,9-tetrahydropyrano[ 3,4- b]indole-l-methanol (X; R CH R R, R, R andnmr(CDCl 81.43(s,3H), 2.68(t, J 5.5 cps,2H), 3.65 (d, J 6 cps, 2H), 3.86(t, J 5.5 cps, 2H), after crystallization from benzene-petroleum ether.

N,N-dicyclohexylcarbodiimide (17.36 g, 0.084 mole) is added to a cooled,stirred solution of the above primary alcohol (6.09 g. 0.028 mole) in 63ml of dimethyl sulfoxide-benzene (2:1) containing trifluoroacetic acid(1.12 ml, 0.014 mole) and pyridine (2.24 ml, 0.028 mole). The reactionis stirred at room temperature under nitrogen for 5 hr. The reactionmixture is now diluted with 600 ml of ether, followed by the dropwiseaddition of a solution of oxalic acid (7.56 g) in 21 ml of methanol.After minutes, water (600 ml) is added and the insoluble material iscollected. The organic phase is washed with water (2X), 5 percentaqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO theorganic phase is evaporated to yield an oil. The oil is purified bychromatography on silica gel. Elution with 10 percent ether in benzeneaffords the title compound as eluate, nmr (CDCl;,) 8 l.59(s,3H),2.84(I,J =5.5 cps, 2H), 4.150, J 5.5 cps, 2H).

pcntaethy1-1-(2- thieny1)//butyric acid.

Oxidation of the latter compound with silver oxide according to themethod of Delpineand Bonnet, cited above, affords l-methyll,3,4,9-tetrahydropyrano[ 3 ,4- b]indole-1-carboxylic acid, nmr (CDCl8l.79(s,3H), 2.83(t,2H), 4.l7(t,2H), 9.20(1H), identical to the productobtained in Example 4.

By following the procedure of Example 169 but using as starting materialan equivalent amount of the appropriate starting material of formula 11,for example, those described in Examples 1 to 168, inclusive, instead oftryptophol, and using an equivalent amount of the appropriateketoalcohol lower alkyl ester of formula V111, then the acid compoundsof formula 1 in which R is hydrogen and Z is hydroxy, for example, therespective products of Examples 1 to 168, inclusive, are obtained.

More specifically exemplified, according to the procedure of Example 169the use of indole-3-ethanethiol and acetonyl acetate affordsl-methyl-1,3,4,9- tetrahydrothiopyrano[ 3 ,4-b]indolel -acetic acid,identical to the product of Example 3. Similarly, the use of tryptopholand S-acetoxypentan-Z-one affords 1- methyl 1,3 ,4,9-tetrahydropyrano[3,4-blindole- 1 -pro- P1 asisitislsat sal i ..r2 .s 9f ixatnele EXAMPLE170 N,N,l-TRlMETHYL-l,3,4,9- TETRAHYDROPYRANO[ 3 ,4-b]-INDOLE- lACETAMlDE (I; R CH R R, R, R, R and R H, X O, Y CH CO AND Z N(CH To astirred solution of 1-methyl-l,3,4,9-tetrahydropyrano[3,4-b]indole-l-acetic acid (15 g, 0.061 mole), preparedas described in Example 1, in dry tetrahydrofuran (300 ml), cooled to-5C, is added triethylamine (18.5 g, 0.183 mole), followed by ethylchloroformate (16.6 g, 0.153 mole). The mixture is stirred at 5C for 2hr. This mixture, which now contains the mixed anhydride of the abovestarting material, is added dropwise to a cooled 40 percent aqueoussolution of the amine, dimethylamine (225 ml). The resulting mixture isstirred at room temperature for onehalf hour. Most of thetetrahydrofuran is evaporated, and the residue partitioned betweenchloroform and water. The organic phase is washed with water, dried oversodium sulfate, and evaporated under reduced pressure. The residue issubjected to chromatography on silica gel. Elution with 20 percent ethylacetate in benzene, followed by crystallization of the eluate from TABLEIv-Qoi ti yed No. of the example in which Product: [(prefix listed belowstarting 1,3, 1,9-tetrahydropyrano material is [3,4-b1-indole-1-(suffixlisted lax prepared Amine be1ow)] prefixl/sullix 236. 1211 (JIIaNHzN,l-dimethyV/propionamide.

M0... 129 N113 l-methyl/lpropionamide.

241. 121) (ClImNII N,Ng-trimethyV/propiona- 242. 129 Yl-CoHnNIIzN-hexyl-l-methyU/propiom mir e.

243.. 12!) (CzlfihNll N,N-dlethyl-l-methyl// propionamide.

2'14 87 (,lhNllz N,l-dimethyl/lcarboxamide.

24F: 87 Nllg 1-mothyl//earboxamidc.

246... 87 ((111%)2N1l N,N,1-trlmethyl//carboxamlde.

.547... 87 Il-(JnllnNlIz N-lifiifyl-l-methyll/carboxa- Ill 0.

248. 87 (C lImNI I N,N-dlethy1-1-methyl// carboxamide.

249... 88 CIIQNHZ N ,3-dlmethyl-1-ethyl/l carboxamlde.

250... 91 NH; 8-ethy1-1-ethynyl// carboxamlde.

251. 92 (CHmNI-I 1-cyclopropyl-N,N-dimethy1- 4-isopropyll/carboxamide.

252... 94 ie iaNHz N-hegyl-l-phenyl//oarboxa- 253... 95 (C2H5):NHl-benzy1-3-methyl-N,N,3-tri ethyU/carboxamlde.

N0. of the example Product [(prefix listed below in which1,3,4,9-tetrahydrothiopyranostarting [3,4-b]lndole-1-(sufi"1x listedmaterial is below)] Prefix//suffix Ex. prepared Amine No. of the exampleProduct [(prefix listed below in which 1,3,4,9-tetrahydrothloyranostarting [8,4-b]lndole-1-(sufilx sted material is below)]Preflx//su1'fix Ex. prepared Amine 254... 97 (OHSMNHN,bfiA-tetramethyll/aceta- 255.. 9B OI'LiNHZl-ethyl-N-methy1//acetomlde.

256... 08 NH3 l-ethyl/lacetamide.

257..- 08 (CHz)zNH N,N-dimethyl-1-ethyl// acetnmide.

258.-- )8 n-CioI-IiaNHz l-ethyl-N-hexyll/acetamido.

250. )8 (C2115) zNII N,N,1-Lriol.hyl/lacctamiclo.

262... ((JlhhNIl N,N-dimctliyl-l-propylll ncotamldo.

N,N-diinethyl-l-propyl/l acetamide.

263... 99 n-CaH NII N-hexyl-l-pr0py1//acetamide.

264... 00 (Cinema N,N -ddiethyl-l-propyll/necta- 266... 100 N11;1-1sopropyll/acctomide.

267-.. 100 (C HQ NII N,N-diotl1yl-1-isopropyl/l acctamide.

268... 102 OIIgNIIz N,3-dimctliyl-1-propyl// acct-amide.

260... 102 NH; 3-motliyl-1propyl/lacetnmido.

270... 102 (CIIQ NII l-propyl, N,3-dimethyl// ocotaniido.

271... 102 n-Cnll N112 N-hexyl-3-metl1yl-l-propyl/l acctamido.

272... 102 (C21I5)2NI'I N,N-diothyl-Zl-methyl-l propyl/lacetamido.

273-.. 104 CHgNHg N,a,1-trimeLhyU/acetamide.

274... 104 NH; aJ-dimethyU/acetamide.

275--. 104 (CHmNH N,Ngx,l-tetramethyl/lacetami e.

276 104 n-CuH NH a,1-d(iimetl1yl-N-hexyll/aceta- 277... 104 (C2H5)2NHN,N-dlethyl-a,1-dimethyl// acetamide.

278... 105 CHgNHz 1-cyclohexyl-N,a,a-trimethyl// aootamide.

279-.. 106 (C2II5)2NII N,Nzidietliyl-l-phenyl/laceta- 281. 111 NH;G-bromo-l-propyl/lacetamide.

282. 117 (CHmNII a-Diethyl-N,N-dimethyl-8- fluor0-1-vinyl//acetnmide.

283... 121 n-CoH NH 1-CYClOpl'ODYl-a,a-diethyl- 3,3-dimethyl-6-ethoxy-N-hexyll/acetamide.

284... 126 (CHa)2NH1-benzyl-N,N,a,a,3-pentamethyl-S-propionoxy/lacetamide.

285 128 OIIaNIIg 1-(2-thienyl)-N,a,a-trimethylllacetmnide.

286... 132 N11 1-cyclobutyl-3-methyl-8-nitroa-propyl/lpropionamide.

287- 137 (CITalzNII 4,4-diethyl-N,N,a,a, 5,3-

hexamothyl-l-nmthallyl/l propionnmidc.

288. 140 (CQIIQZNH N ,N-dfllyl-5-11101110xy-ormothyl-l-phenyl-3-propyll/propionnmide.

propynyl)-3.3,5'triethyl// propionamide.

TAB LE 1V Continued No. of the w example in which Product: [(prefixlisted below starting 1.3 .4.9-tetrahydropyrano 5 material is[SA-bI-indoIe-l-(suffix listed Ex. prepared Amine below) lprefix/suffix290- 146 l-cyclopropyl-mfldivl ll \l-6- -N 11; \l boxy-N -phi n \'l;/propionmnido.

291... 150 (CHilgNII N,N.l-trimelhylf/bntyrnmidv. 292. 150 CHaNHN,1-dimvthylf/bulyrmnido.

293- 150 l-nietliyl-N-phenyl/l N Hg butyrainide.

204 150 1'1'C6I{13NH2 N-hexyl-1-methyl//butyramide' 295 153 011mmfi-myA- m py 3,3- l 5 tr1methy1-1-vu1yl/l butyramide. 296 154 (C2I'I5)QNH l-allyl-N,N-diethyl-flfl wtetramethyl/lbutyrannde. 297- 155 (CHQ NI-I7-01110lO-N,N,a,fi,B,'y,"/,4,4- nonamethyl-l-ethynyl/l butyramitle. 208159 NH; 5-br0mo-1-cyelopentyl-a-a,6- trimetliyl/lbutyrainide.

299 161 C:H3N H N,a-dimethyl-8-etliyl 1- phenyH/butyramide. 300- 163(CQII5)2N II 1-phe1iyl-N,N,u,'y'tetraethyl- 3,3,5-trimethyl//butyram1de.301 165 n-CsHiaN H2 l-benZyl-a,fl-diethy13,3-

dimethyl'N-liexyl-5-propyl// 1 butyramide. 302. 168 CHgNH7-chl0r0-N-methyl- ,a,3,4,4-

pentaethyl-1-(2-th1enyl)// butyramide.

EXAM PLE 303 l-METHYL-l ,3 ,4,9-TETRAHYDROPYRANO[ 3 ,4-

b]lNDOLE-l-CARBOXAMIDE (l; R CH R R R, R R AND R H, X O, Y =CO AND Z NHBy following the procedure of Example 1 but using an equivalent amountof pyruvamide instead of ethyl acetoacetate, l-methyl-l,3,4,9-tetrahydropyrano[ 3,4- blindole-l-carboxamide, m.p. l88189C.after recrystallization from benzene-hexane, identical with the productof Example 177, is obtained.

In the same manner but using an equivalent amount of the appropriatestarting material of formula II in place of tryptophol together with theappropriate a-, [3-, yor d-ketoamide, the products listed in Tables Illand 1V may be obtained. For example, by using tryptophol (ll; R R, R, RR H and X OH) and the ,B-ketoamide, N,N-dimethyl-acetoacetamide, in theprocedure of this Example, N,N,l-trimethyl-l,3,4,9-tetrahydropyrano[3,4-b]indole-l-acetamide, identical with the product ofExample 170, is obtained.

EXAMPLE 304 1,9-DlMETHYL- 1 ,3,4,9- TETRAHYDROPYRANO[3,4-b]lNDOLE-1-ACETIC ACID (l; R AND R CH R R, R, R AND R =H,X=H,X=O,Y=CH CO ANDZ=OHl-Methyll ,3 ,4,9-tetrahydropyrano[ 3 ,4-b indolelacetic acid (10 g.,0.04 mole), prepared as described in Example 1, in ml. oftetrahydrofuran is added dropwise to a stirred suspension of sodiumhydride (4.4 g. of 55 percent dispresion) in 200 ml. of oftetrahydrofuran. This mixture is heated at 50C. with stirring for 2 hr.Methyl iodide (14.2 g. 0.1 mole) is added dropwise and heating andstirring is continued for a further 2 hr.

After cooling, water is added until the solution is clear. Thetetrahydrofuran is evaporated off under redried over sodium sulfate andtreated with charcoal. 5

The organic layer is evaporated. The residue is crystallized frombenzene and then ether-petroleum ether to afford the title compound,m.p. 105 108C., nmr (CDC1 6 1.73 (S,3H), 2.83 (t, J 5.5, 21-1), 3.0(2H), 3.68 (3H), 4.08 (t, J =5.5, 21-1), 7.34 (4H), 9.47 (1H).

By following the procedure of Example 304 but using the startingmaterial an equivalent amount of the acid compounds of formula 1,compounds of formula 1 in which R is hydrogen and Z is hydroxy,described in Examples 1 to 168, inclusive, instead of 1-methy1-1,3,4,9-tetrahydropyrano[3,4-bl-indo1e-l-acetic acid, and using an equivalentamount of an appropriate lower alkyl or lower alkenyl halide, then thecorresponding N-alkylated acid compounds of formula I in which R islower alkyl or lower alkenyl are obtained. Examples In the same mannerbut replacing methyl lodlde with of these latter compounds are listed asproducts in Taan equivalent amount of ethyl iodide, or propyl iodidebles V and VI together with the appropriate starting9-ethyl-1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]inmaterial and alkyl oralkyl halide used for their prepadolel-acetic acid and1-methyl-9-propyl-1,3,4,9- ration. In each case the starting material 15noted by the tetrahydropyrano[3,4-b]indo1e-l-acetic acid are obl 5Example in which it 18 prepared. tained, respectively.

TABLE V NO. OF THE PRODUCT: [(PREFIX LISTED BELOW- EXAMPLE IN WHICHl,3,4,9 TETRAHYDROPYRANO[3.4-h]- STARTING MATERIAL IS ALKYL ORINDOLE-(SUFFIX LISTED BELOWII ALKENYL EXAMPLE PREPARED HALIDEPREFIXl/SUFFIX 305 l CH CHCH Br 9-allyl-1-methyll/acetic acid.

m.p.103 105C.

306 1 CH,=CHBr 1-methy1-9-viny1l/acetic acid 307 1 CH,=C(CH;,)CH,Brl-methyl-9-methalIyl/lacetic acid 308 2 n-C,H I1-methyl-9-propy1//propionic acid 309 2 CH l 1,9-dimethyl/lpropionicacid 310 2 CH,=CHBr 1-methyl-J-vinyI/lprupionic acid 31 1 2 cmcnciucl9-alIy1-1-methyl//propionic acid 312 4 CH I 1,9dimethy1//carboxylic acid313 4 CH =CHBr 1-methy1'9viny1//carhoxy1ic acid 314 7 CH I fi-hydroxy- 1-propeny1 )3,3,9-

trimethyl/lcarhoxylic acid 315 9 CH CH=CHBr 1-cyclopropyl-4-isopropy1-9(1-propenyl)//carboxylic acid 316 1 1 i-C H,l9-isopropy1'1-pheny11//carboxylic acid 317 15 CH l1-ethyl-9-methyll/acetic acid 318 15 C H Cl 1.9-dielhyll/acetic acid 31915 CH,=CHCH,Br 9-allyl-l-ethyll/acetic acid 320 15 CH =CHBr1-ethy1-9-viny1l/acetic acid 321 16 CH I Q-methyl-l-propyll/acetic acid322 16 n-C H,Cl 1.9-dipropy1//acetic acid 323 I6 CH CHCH Br 9-allyl-lpropyl/[acetic acid 324 I6 CH,=C(CH,)CH,Br 9-methallyl-l-prupyIl/aceticacid 325 17 CH,[ 9-methy1-1-isopropyll/acetic acid 326 17 CH CHBrl-isopropyI-9-viny1/lacetic acid 327 19 n-CJH Cl1.Q-dipropyl-3-methyll/acetic acid 328 19 CHfiHCHJSr9-al1yl3methyl'1-propyl//acetic acid 329 21 CH,! a.l,9-trimethyl//aceticacid 330 21 CH,=CHBr 0,1-dimethy1-l-vinyllllacetic acid 331 22 n-C H C11-cyclohexyl-ma-dimethyLQ- propyl/lacetic acid 332 27 CH,=CHCH 19-allyl-l'(2-thienyl)//acetic acid 333 29 CH Cl1,9-dimethyl-(a-methoxy/lacetic acid 334 34 CH =CHBr 6-nitro-l:propyl-Q-vinyl/l acetic acid

1. A COMPOUND OF THE FORMULA:
 2. A compound of the formula: 3.N,N,1-Trimethyl-1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetamide, asclaimed in claim
 2. 4.1-Methyl-1,3,4,9-tetrahydropyrano(3,4-b)-indole-1-acetamide, as claimedin claim
 2. 5.N,1-Dimethyl-1,3,4,9-tetrahydropyrano(3,4-b)indole-1-acetamide, asclaimed in claim
 2. 6.N-Phenyl-1-methyl-1,3,4,9-tetrahydropyrano(3,4-b)indole-1-acetamide, asclaimed in claim
 2. 7.N,1-Dimethyl-1,3,4,9-tetrahydropyrano(3,4-b)indole-1-propionamide, asclaimed in claim
 2. 8.1-Methyl-1,3,4,9-tetrahydropyrano(3,4-b)indole-1-carboxamide, as claimedin claim 2.